Miscellaneous structures

Novel structures are now appearing in the patent literature. A series of hydro-xamic acids, such as 33 (IC50 = 100 nM, human) were disclosed in a recent application [76]. In another patent application [61] the LJPC group claimed a series of p-amidoamines, including 34. This compound was a very potent inhibitor of rat lung SSAO/VAP-1 (IC50 = 33 nM, respectively). Interestingly, it was described as an irreversible inhibitor of the enzyme. A series of amide derivatives of proline were reported [75] to be very potent inhibitors of the human enzyme. For example, 35 was stated to have an IC50 value = 78 nM.

Patent applications from Astellas Pharma [77,78] and Fujisawa [79] have disclosed series of guanine, imidates and aminoimidazoles built on a bis arylethane core structure. Some of these are very potent. Compound 36 inhibits the human and rat enzymes with IC50 = 150 nM and 12 nM, respectively; compounds 37, 38 and 39 inhibit human SSAO/VAP-1 with IC50 = 5.7nM, 5.3nM and 2.4nM, respectively.

Other inhibitors include alginic acid hydroxamates [80], the natural products myricetin galloylglycosides [81], polyaminoglycosides [82] and a number of antidepressant drugs [83] which demonstrate various degree of SSAO/VAP-1 inhibitory property in rats, humans and cows.

SSAO/VAP-1 is an emerging target for drug discovery. There is considerable scientific evidence pointing to this protein as a potential target for many inflammatory diseases. The target is amenable to drug discovery, and a considerable effort to discover novel, useful drug candidates is underway. However, there is reason to question the validity of this target. Drugs such as hydralazine and phenelzine which inhibit SSAO/VAP-1 at therapeutic doses have not been reported to have anti-inflammatory properties. True validation will only come when some of the newer, very potent and selective agents are evaluated in patients suffering from these inflammatory conditions.

This is an exciting time for those seeking to better understand the precise mechanistic details by which SSAO/VAP-1 serves to facilitate inflammatory cell migration. In particular, if the natural ligand or ligands can be determined, this should elevate the profile of this inflammatory target as a drug target comparable to the selectins and integrins. This knowledge may also help with the design of more potent and selective inhibitors.

The search for drug leads is an interesting endeavor in itself. Time will tell whether a potent competitive inhibitor will have advantages over time-dependent, irreversible inhibitors, or whether the latter class will be more effective against this inducible protein. In any case, the availability of the crystal structure of a truncated human form of the protein will facilitate the search for structural cores which may lead to novel competitive inhibitors. Finally, since SSAO/VAP-1 is a protein which can facilitate cell-cell interaction and can oxidize a family of primary amines, there are in effect two targets for drug design -antagonize the adhesion binding site or inhibit the amine oxidase activity. Both would appear to be valid approaches.

Although most work to date has focused on the enzyme inhibition aspect, it is possible that the monoclonal VAP-1 antibody discussed above may well be closer to the clinic. The task of designing small molecules to interfere with cell-cell recognition is certainly feasible, but this will not be a trivial effort, more akin to the search for selective selectin antagonists which has proven to be very challenging. As confidence grows in the pharmaceutical industry that SSAO/VAP-1 is a validated target, it is inevitable that considerable resources will be directed to all avenues to block the functional action of this protein.

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